Rabbits develop aortic atherosclerosis when fed a diet high in cholesterol. The type of lesions closely resemble types I-III atherosclerotic lesions in man. We have generated rabbits overexpressing potentially therapeutic genes relevant to the metabolism of the anti-atherogenic high density lipoprotein. Human apolipoprotein A-I and lecithin-cholesterol acyl transferase transgenic rabbits have increased in the concentration of high density lipoprotein. Since rabbit lipoprotein metabolism and susceptibility to dietary atherosclerosis closely parallels that of man, we have undertaken the generation of rabbits transgenic for the human enzyme lecithin-cholesterol acyl transferase. We have generated 3 founder lines of rabbits integrating and expressing this gene. As with mice and man, the principal sites of synthesis are the liver and brain. The total and high density lipoprotein cholesterol and apolipoprotein A-I concentrations are increased 2-3 fold that of controls in the highest level of expression. In addition, there is a virtual disappearance in the concentration of the apolipoprotein B-containing particles. Metabolic turnover studies indicate that these changes in the particle concentrations of these particles is due to altered clearance from the circulation. The altered metabolism of these particles is directly correlated with the extent of expression of this enzyme. Rabbits with high, intermediate, and low levels of plasma lecithin-cholesterol acyl transferase expression have parallel degrees of alteration in the fractional catabolic rates of these particles from the circulation. Nontransgenic rabbits fed a high cholesterol diet have a marked increase in the concentration of the atherogenic very low, intermediate, and low lecithin-cholesterol acyl transferase have substantially higher concentrations of high density lipoproteins and lower concentration in the atherogenic very low, intermediate, and low density lipoprotein particles. We have found that overexpression of lecithin-cholesterol acyl transferase prevents the development of atherosclerosis induced by cholesterol-feeding rabbits.